The most practical animal model for HIV-1 infection in humans consists of infection of rhesus macaques by SIX/MAC or chimeras encoding the HIV-1 envelope (SHIV), both of which cause AIDS in animals. However, despite the parallels between HIV-1 infection of humans and SIVMAc/SHIV infection of macaques, the fact that SIVmac is a distinct virus compared to HIV-1 limits the usefulness of this animal model. HIV-1 cannot infect rhesus macaques at least in part due to blocks in the viral replication cycle that have been identified in macaque derived cells in vitro. Based on an understanding of species-specific restriction factors we have generated new chimeras between HIV-1 and SIVMAc containing more HIV-1-derived sequences than any SHIV developed to date. These HIV/SIVMAc chimeras replicate very efficiently in rhesus macaque PBMC. In aim 1 of this proposal we will generate versions of our HIV/SIVMAc chimeras that express HIV-1 envelope proteins with different tropisms. These viruses will be tested for in vivo replication in rhesus macaques. In aim 2 we will attempt to generate viruses that are as homologous to HIV-1 as possible but are capable of replicating in rhesus macaque cells. If successful these studies may lead to the derivation of important HIV-1 animal models that will facilitate the evaluation of new drug and vaccine therapies. Relevance to public health: HIV-1, the predominant cause of AIDS in humans, is unable to replicate in most nonhuman primate species and current animal models are limited. We have developed novel chimeric viruses based on HIV-1 and are proposing to test their utility as an HIV-1 infection model in rhesus monkeys and to generate additional HIV-1-derived viruses. If successful, this proposal will lead to improved animal models for HIV-1 infection and will considerably facilitate the development and testing of drug and vaccine interventions. [unreadable] [unreadable] [unreadable]